A study of the stereochemical features of 5-endo-trig iodocyclisations of 2-alkenyIcycloalkan-1-ols

Article abstract of DOI:10.1039/b004684l

Overall 5-endo-trig iodocyclisations of all isomers of the 2-alkenyIcyclopentan-l-ols and -cyclohexan-1-ols 11,12,14 and 16 have been examined. Only in the cases of the trans-alkenylcyclopentanols lia and 12a are the reactions either unsuccessful or low y

Full text of DOI:10.1039/b004684l

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A study of the stereochemical features of 5-endo-trig
iodocyclisations of 2-alkenylcycloalkan-1-ols
Jenny M. Barks,a Gordon G. Weingartenb and David W. Knight*†a
1
a Chemistry Department, University Park, Nottingham, UK NG7 2RD
b Glaxo Wellcome Research and Development Ltd., Medical Research Centre, Stevenage,
UK SG1 2NY
Received (in Cambridge, UK) 13th June 2000, Accepted 10th August 2000
First published as an Advance Article on the web 3rd October 2000
Overall 5-endo-trig iodocyclisations of all isomers of the 2-alkenylcyclopentan-1-ols and -cyclohexan-1-ols 11, 12, 14
and 16 have been examined. Only in the cases of the trans-alkenylcyclopentanols 11a and 12a are the reactions either
unsuccessful or low yielding, by reason of formation of a relatively strained trans-fused 5/5 ring system. In contrast,
iodocyclisations of cis-alkenylcyclopentanols work well but only show useful stereoselection in the case of the cis-
(Z )-alkenylcyclopentanol 16a. All examples involving the cyclohexanols 14 and 16 are high yielding and generally
lead to single isomers of perhydro-3-iodobenzofurans 18, 20, 23 and 26. Transition state conformations are proposed
which account for these observations and which should be useful in applying this type of cyclisation to related
substrates.
During the past few years, overall 5-endo-trig cyclisations
have become established as synthetically useful and often
highly stereoselective processes for the elaboration of saturated
five-membered heterocycles.1–3 In the case of the (E)-homo-
allylic alcohols 1, such cyclisations can be effected by treat-
ment with three equivalents each of iodine and sodium
hydrogen carbonate in dry acetonitrile and lead, highly
selectively, to the tetrahydrofuran diastereoisomers 2. These
conditions are based on those originally developed by
Bartlett and co-workers4 during their studies of iodolactoniz-
ation reactions. In the present examples, the use of anhydrous
conditions appears to be essential: if water is present, the
major products are the iodohydrins derived from the
homoallylic alcohols 1. In contrast to the generally rapid
cyclisations of the (E)-isomers 1, similar reactions of
the corresponding (Z)-isomers are much slower and give
poorer yields of the all-cis trisubstituted tetrahydrofurans 3,
but again as single diastereoisomers. These observations are
consistent with the intermediacy of the chair conformation 4,
controlled by the equatorial position of the substituent R; the
poorer cyclisations of the (Z)-isomers of alcohols 1 are thus
explained by the necessarily axial positioning of the alkene
substituent Z. We were intrigued by the prospect that this
type of cyclisation could be extended to the formation of
ring-fused tetrahydrofurans
2-alkenylcycloalkanols 5.5 However, at the outset, extra-
polation of the transition state model to the more
6 from stereoisomers of the
Results and discussion
4
The necessary starting materials 11, 12, 14 and 16 were readily
prepared from epoxycyclopentane and epoxycyclohexane
respectively [9; n = 1, 2] (Scheme 1). Yamaguchi–Hirao alkyl-
ation7 of lithiohexyne using these electrophiles with boron
trifluoride–diethyl ether as the activating species led to good
isolated yields of the trans-2-alkynylcycloalkanols 10. Direct
reduction using lithium aluminium hydride in refluxing
tetrahydrofuran–toluene8 then gave the first pair of precursors,
the trans-(E)-isomers 11. Lindlar reduction gave the corre-
sponding trans-(Z)-isomers 12, both in excellent yields. The
related cis-isomers, 14 and 16, were accessed by a smooth
Mitsunobu inversion9 of the initial alkynols 10 using
p-nitrobenzoic acid as the nucleophile.10 Treatment of the
constrained analogues 5 gave unclear indications regarding
the prospects for success; while the 1,2-trans-isomers appeared
to be very well set up for cyclisation via conformation 7,
it was far from clear whether the related cis isomers would
undergo cyclisation at all, as the two reacting centres
appeared rather distant in the anticipated initial reacting
conformation 8. In the event, most of the cyclisations
were very successful; herein, we report full details of these
findings.6
† Present address: Chemistry Department, Cardiff University, PO Box
912, Cardiff, UK CF10 3TB.
DOI: 10.1039/b004684l
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This journal is © The Royal Society of Chemistry 2000
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we examined a few alternative conditions using substrate 11b.
We found that powdered sodium hydroxide could be used
as the base, in place of sodium hydrogen carbonate, without
reducing the yield. The cyclisation also worked, but slightly less
efficiently (~ 80% isolated yield), in the absence of base; hence,
in such favourable examples, competing iodohydrin formation
is not especially deleterious although clearly in examples con-
taining more sensitive functionality, exposure to the hydrogen
iodide generated during the cyclisation could be a significant
drawback. N-Iodosuccinimide was also effective as an iodo-
nium source, but cyclisation was some five times slower.
Perhaps surprisingly, when either triethylamine or N,N-diiso-
propylethylamine (Hünig’s base) was used as the base in place
of sodium hydrogen carbonate, no cyclisation was observed
even after prolonged exposure to three equivalents of iodine.
The requirement of three equivalents of iodine suggests that
more complex species than simply iodonium ions are necessary
for these and related cyclisations1,3,4 and that these are not
present when tertiary amines are used as base; in all cases, use
of less than three equivalents resulted in incomplete conversion,
as had been noted previously.1,3 Returning to the original
substrates, it was next found that the trans-(Z)-cyclopentanol
12a failed to cyclise to give isomers of the trans-fused system
19, whereas the corresponding cyclohexanol 12b underwent
smooth but slow cyclisation, relative to the related trans-(E)-
isomer 11b, to give the perhydrobenzofuran diastereoisomer
20. Our model work1 had revealed that (Z)-homoallylic
alcohols in general are relatively poor substrates for this type
of cyclisation (see above and structure 4). It seems likely there-
fore that a similar effect applies in these two cases which involve
the (Z)-isomer of conformation 7. In the case of the cyclo-
pentanol 12a, a combination of this and the additional
requirement of formation of a trans-fused 5/5 bicyclic system
19 proved just too much to permit the cyclisation to proceed.
That the less strained trans-5/6 bicycle 20 was formed in
good yield but at a much slower rate, relative to cyclisation of
the corresponding trans-(E)-isomer 11b, is probably just a
reflection of a higher energy transition state brought about by
the pseudoaxial positioning of the butyl side-chain.
Scheme 1 Reagents and conditions: i, BuCCLi, BF3ؒOEt2, THF,
Ϫ78 ЊC; ii, LiAlH4, THF–toluene, reflux; iii, H2, 5% Pd-C, quinoline,
EtOAc, 20 ЊC; iv, p-NO2C6H4CO2H, Ph3P, EtO2CN᎐NCO2Et, THF,
᎐
20 ЊC; v, NaOH, MeOH, 20 ЊC.
resulting esters 13 with lithium aluminium hydride, by the
foregoing method, both removed the ester group and reduced
the alkyne to give the required cis-(E)-alkenylcycloalkanols 14,
while saponification of esters 13 followed by Lindlar reduction
of the resulting alkynols 15 gave the final members of the series,
the cis-(Z)-isomers 16.
The central cyclisations were performed under a standard
set of conditions,1,4 consisting of exposure of the substrates 11,
12, 14 and 16 to three equivalents of iodine in dry acetonitrile
containing three equivalents of sodium hydrogen carbonate at
0 ЊC. The trans-(E)-alkenylcyclopentanol 11a underwent rather
slow cyclisation and it was only after approximately 48 hours
that the starting material has all reacted according to TLC
analysis, which indicated the formation of an ominous number
of products. A simple aqueous work-up followed by chromato-
graphic separation delivered a single hexahydrocyclopenta-
[b]furan 17 in 29% isolated yield, the structure of which was
deduced as outlined below. Other products appeared to be the
corresponding iodohydrins, presumably formed as water was
generated during the cyclisation leading to the bicycle 17,
although the addition of drying agents such as molecular sieves
or magnesium sulfate failed to improve the yield. On reflection,
we realised that this could be regarded as a remarkable result,
in that the relatively strained trans-fused 5/5 ring system in 17
had been formed at all. Further, the relative stereochemistry
was consistent with a reacting conformation based on that anti-
cipated (7) from initial studies.1 This was borne out when the
corresponding cyclohexane derivative 11b was similarly exposed
to iodine: in this case, cyclisation occurred to give a single
perhydrobenzofuran 18 in essentially quantitative yield in
about one hour at 0 ЊC. This was consistent with the formation
of a much less strained trans-fused 6/5 ring system during
cyclisation, again via a transition state related to conformation
7. Despite the excellent yield obtained from this cyclisation,
We then turned to the corresponding cis-alkenylcyclo-
alkanols 14 and 16, not certain if these would undergo cyclis-
ation at all, in view of the likely initial conformation 8. In the
event, cyclisations of the cis-(E)-cycloalkanols 14a and 14b
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Fig. 1
64 and 77% respectively, of the formyloxy derivatives 34 and 35.
In both cases, the reactions proceeded with complete inversion.
This is in direct contrast to the observation made by Bartlett
and Ting11 that a similar reaction of the annulated iodotetra-
hydropyran 36 led to the corresponding formyloxy derivative
37 but with retention of configuration. This latter result can be
explained by assuming anchiomeric assistance from the ring
oxygen and hence the intermediacy of the oxonium species 38
and a double inversion process. Presumably, in the present
cases, a similar intermediate 39 is not involved as it is just too
strained and hence formation of the observed products 34
and 35 proceeds by a straightforward SN2 process. The 2,3-
trans stereochemistry in the substrate 18 did not appear to
hinder the displacement and formation of the 2,3-cis product
35 was equally facile, at least to a first approximation. This
mechanism is also involved in the formation of the azide 40
and the sulfide 41 from perhydroiodofuran 18; again, the un-
optimised yields were acceptable and formation of the more
hindered 2,3-cis isomers did not seem to inhibit the displace-
ment significantly. Clearly, these transformations provide an
additional set of options for using the initial iodocyclisation
products in synthesis.
turned out to be somewhat too facile, being both relatively
rapid and giving mixtures of products. The cis-fused hexa-
hydrocyclopenta[b]furans 21 and 22 were obtained in a 1.25:1
ratio, slightly improved by performing the cyclisations at
Ϫ78 ЊC. At this lower temperature, the cyclisations took up to
five hours to go to completion and the addition of dichloro-
methane was used to prevent the reaction mixture from
freezing. Similarly, the two cis-fused perhydrobenzofuran iso-
mers 23 and 24 were obtained from the cis-(E)-cyclohexanol
14b but in a more useful ratio of 5:1 at 0 ЊC, improved to
ca. 10:1 at Ϫ78 ЊC. Hence, such cyclisations are indeed viable
and, assuming an initial major conformation 8 for these sub-
strates, suggest that a late transition state is involved based on
the conformation 27 (Fig. 1). The minor isomer 24 could then
arise via the less favourable conformation 28 which would lead
to the iodonium ions 29 and 30 and thence to the observed
minor product. The much poorer stereoselection obtained from
the cyclopentanol 14a is presumably a reflection of the lower
energy differences between related conformations in a five-ring
system. By contrast, the final series, the cis-(Z)-cycloalkanols
16, appeared to have just the right balance between favourable
(formation of a cis-fused ring system) and unfavourable (cyclis-
ation onto a (Z)-alkene) factors. Cyclisations were relatively
slow but very clean and gave > 90% isolated yields of the single
diastereoisomers 25 and 26, consistent with conformation 31
(Fig. 1). The more sterically demanding (Z)-alkene function
presumably renders the alternative conformation 32, in which
the C–OH and alkenyl substituent bonds are aligned in
parallel fashion, inaccessible, at least at the present reaction
temperature.
We also briefly examined the related bromocyclisation
reaction and found that the trans-(E)-cyclohexanol 11b could
be transformed into the bromoperhydrobenzofuran 33 with the
same excellent level of stereoselectivity but required reaction
in refluxing carbon tetrachloride when N-bromosuccinimide
was the bromonium ion source. The detailed structure of this
bromo analogue 33 was deduced by comparison between its
spectral data and those of the corresponding iodo derivative
18 (see below). Finally, partly to extend the synthetic utility of
these cyclisations and also to provide additional structural
proof of the initial products, we examined methods for the
displacement of the iodine by other heteroatoms. Firstly,
treatment of the perhydroiodofurans 20 and 18 with silver
tetrafluoroborate in hot DMF11 gave reasonable isolated yields,
In all the foregoing cases, once the basic molecular formulae
had been established from the usual analytical and spectro-
scopic data, the detailed structures and stereochemistries were
ascertained using extensive NMR experiments. Firstly, it was
vital to prove that the products were in fact ring-fused iodotetra-
hydrofurans rather than the isomeric oxetanes 43, which could
arise from 4-exo cyclisations of the precursors 42. Initially,
this was done by assigning a high field methine resonance in the
13C NMR spectrum, positioned around 30 ppm due to a heavy
1
atom effect,12 to the CHI group. By a combination of H–1H
1
and H–13C correlation spectra, this was clearly shown to be
positioned between two other methines, one between 75 and
90 ppm and the other at around 30 ppm, assigned to the 2-CHO
and 3a-CH groups, clearly precluding the oxetane structures
43. The remaining methine resonance in the 13C spectra
was then correlated with the other ring junction CHO methine
carbon. The remaining features of the spectra, together with
coupling constant correlations then confirmed the assigned
structures as annulated tetrahydrofurans. Finally, difference
nuclear Overhauser enhancement spectra were used to
assign the respective stereochemistries, some examples of which
are shown in Fig. 2 in which only the positive differences of
>2% are shown. Other compounds in the series gave much
the same results, as detailed in the Experimental section,
J. Chem. Soc., Perkin Trans. 1, 2000, 3469–3476
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into the precursors without a deleterious effect upon the
cyclisation, as could additional heteroatoms, especially at
various positions in the initial ring.
Experimental
Infrared spectra were recorded using a Perkin-Elmer 1720
FTIR instrument for thin films between NaCl plates. 1H NMR
spectra were recorded using a Bruker WM 250 PFT (250),
a JEOL EX270 PFT (270) or a Bruker AM 400 PFT (400)
spectrometer. Coupling constants are quoted in hertz. 13C
spectra were recorded using the same instruments operating at
62.5, 67.5 and 100 MHz respectively. All spectra were recorded
using dilute solutions in deuteriochloroform with tetramethyl-
silane as an internal standard. Molecular weights and mass
spectra were determined using either a VG 7070E or an AEI
MS 902 spectrometer, operating in the electron impact mode,
unless otherwise stated. All reactions were performed under an
atmosphere of dry nitrogen unless otherwise stated and, where
appropriate, in oven-dried glassware. All solvents were purified
and dried using standard methods.13 Petrol refers to the fraction
with bp 40–60 ЊC. Ether refers to diethyl ether. CC indicates
column chromatography using SORBSILR (40–60 µm) silica
gel. All solutions from work ups were dried by brief exposure to
dried magnesium sulfate followed by filtration.
Fig. 2
trans-2-(Hex-1-ynyl)cyclopentanol 10a
Butyllithium (21.0 ml of a 1.6 M solution in hexanes, 33.6
mmol) was added dropwise during 0.25 h to a stirred solution
of hex-1-yne (3.86 ml, 33.6 mmol) in dry tetrahydrofuran
(50 ml), cooled in a solid carbon dioxide–acetone bath. After
an additional 20 min at Ϫ78 ЊC, boron trifluoride–diethyl
ether (2.75 ml, 22.4 mmol) was added dropwise during 5 min
and the resulting solution stirred for a further 10 min, before
the addition of a solution of cyclopentene oxide 9a (1.95 ml,
22.4 mmol) in dry tetrahydrofuran (5 ml) during 2 min. The
resulting mixture was stirred for 1.3 h at Ϫ78 ЊC then quenched
by the addition of saturated aqueous ammonium chloride
(50 ml). The resulting mixture was separated and the aqueous
layer extracted with ethyl acetate (3 × 50 ml). The combined
organic solutions were dried and evaporated. CC (25% ether–
petrol) of the residue gave the hydroxyacetylene 10a (2.30 g,
62%) as a pale yellow oil, νmax/cmϪ1 3425, 2959, 2873 and 2204;
δH (250 MHz) 0.90 (3H, t, J 6.5, CH3), 1.90 (1H, br s, OH),
1.26–2.22 (12H, m), 2.54 (1H, m, 2-H) and 4.11 (1H, m, 1-H);
δC (67.5 MHz) 13.6 (CH3), 18.4, 21.8, 22.1, 31.1, 31.3, 33.2
(all CH2), 38.8 (2-CH), 79.6 (1Ј(2Ј)-C), 81.3 (2Ј(1Ј)-C) and 81.9
(1-CH): m/z 166 (Mϩ, 1%), 148 (6), 123 (14), 106 (51), 91 (58),
80 (100), 79 (71) and 67 (68) [Found: Mϩ, 166.1379. C11H18O
requires M, 166.1358].
trans-2-(Hex-1-ynyl)cyclohexanol 10b
thus putting the structural assignments on a firm footing.
Similar tactics, especially comparative coupling constant data
and difference NOE measurements, were used to deduce the
stereochemistries of the derived 3-substituted analogues 33–35,
40 and 41.
The foregoing method, when applied to cyclohexene oxide 9b
(4.00 ml, 39.5 mmol) with all other quantities appropriately
scaled, gave the hydroxyacetylene 10b (4.43 g, 62%) as a colour-
less oil, νmax/cmϪ1 3406, 2932, 2859 and 2234; δH (270 MHz)
0.90 (3H, t, J 7.1, CH3), 1.08–2.19 (15H, m), 2.67 (1H, br s, OH)
and 3.37 (1H, ddd, J 9.4, 9.4 and 3.9, 1-H); δC (100 MHz) 13.7
(CH3), 18.5, 22.0, 24.4, 25.0, 31.2, 31.5, 33.0 (all CH2), 39.2
(2-CH), 74.0 (1-CH), 81.2 (1Ј(2Ј)-C) and 82.9 (2Ј(1Ј)-C);
m/z 180 (Mϩ, 2%), 162 (5), 137 (27), 120 (44), 105 (35), 95 (54),
91 (72), 84 (59), 79 (81) and 67 (100) [Found: Mϩ, 180.1549.
C12H20O requires M, 180.1514].
In conclusion, these studies indicate that such overall 5-
endo-trig cyclisations represent a generally useful approach to
most of the isomers possible for this type of bicyclic system.
Although there will clearly be some limitations, the mild con-
ditions suggest that many substituents could be incorporated
(1ꢀ,2ꢁ,E)-2-(Hex-1-enyl)cyclopentanol 11a
Lithium aluminium hydride–bis(tetrahydrofuran) complex
(7.67 ml of a 1.0 M solution in toluene, 7.67 mmol) was added
dropwise during 2 min to a stirred solution of the hydroxy-
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acetylene 10a (0.49 g, 2.95 mmol) in dry tetrahydrofuran (20
ml) and dry toluene (20 ml) at ambient temperature and the
resulting mixture stirred at reflux for 48 h. The cooled, stirred
mixture was treated cautiously with ethyl acetate (20 ml) and
water (20 ml). After 10 min, the two layers were separated
and the aqueous layer extracted with ethyl acetate (3 × 30 ml).
The combined organic solutions were dried and evaporated to
leave the trans-(E)-cyclopentanol 11a (0.432 g, 87%) as an oil,
νmax/cmϪ1 3352, 2957, 2928, 2871 and 968; δH (250 MHz) 0.89
(3H, t, J 6.9, CH3), 1.21–2.19 (13H, m), 2.21–2.31 (1H, m, 2-H),
3.77–3.85 (1H, m, 1-H), 5.31 (1H, dd, J 15.3 and 8.0, 1Ј-H) and
5.52 (1H, ddd, J 15.3, 6.7 and 6.7, 2Ј-H); δC (67.5 MHz) 13.9
(CH3), 21.0, 22.1, 29.9, 31.6, 32.3, 33.3 (all CH2), 51.8 (2-CH),
78.5 (1-CH), 131.3 (᎐CH) and 131.8 (᎐CH); m/z 168 (Mϩ, 4%),
28.9 mmol) and 4-nitrobenzoic acid (4.82 g, 28.9 mmol) in dry
benzene (100 ml) at ambient temperature. After 24 h, the
solvent was evaporated and the residue subjected to CC (25%
ether–petrol) to give the nitrobenzoate ester 13a (1.88 g, 99%)
as a yellow oil, νmax/cmϪ1 3044, 2959, 2934, 2870, 2739, 1719,
1529, 1349 and 747; δH (250 MHz) 0.67 (3H, t, J 6.8, CH3),
0.90–2.10 (12H, m), 2.80–2.82 (1H, m, 2-H), 5.42–5.43 (1H,
m, 1-H) and 8.16–8.25 (4H, m, Ar-H); δC (67.5 MHz) 13.4
(CH3), 18.3, 21.7, 22.2, 30.9, 31.3, 31.6 (all CH2), 36.2 (2-CH),
78.2 (1-CH), 78.2 (1Ј(2Ј)-C), 83.0 (2Ј(1Ј)-C), 123.3 (2 × ArCH),
130.7 (2 × ArCH), 136.2 (ArC), 150.4 (ArC) and 164.0 (CO);
m/z [CI–CH4] 316 (Mϩ ϩ H), 286, 279, 263, 194 and 138.
The foregoing ester 13a (0.08 g, 0.25 mmol) was reduced
using lithium aluminium hydride–bis(tetrahydrofuran) com-
plex (0.65 ml of a 1.0 M solution in toluene, 0.65 mmol) exactly
as described above for the reduction of hydroxyacetylene 11a
to give the cis-(E)-cyclopentanol 14a (0.038 g, 92%) as an oil,
νmax/cmϪ1 3408, 2956 and 971; δH (250 MHz) 0.90 (3H, t, J 6.7,
CH3), 1.16–2.10 (12H, m), 2.37–2.46 (1H, m, 2-H), 4.08–4.12
(1H, m, 1-H), 5.54 (1H, dd, J 15.6 and 11.0, 1Ј-H) and 5.56 (1H,
ddd, J 15.6, 5.9 and 5.9, 2Ј-H); δC (67.5 MHz) 13.9 (CH3), 22.0,
22.2, 27.9, 31.7, 32.5, 33.8 (all CH2), 48.7 (2-CH), 75.4 (1-CH),
128.4 (᎐CH) and 133.5 (᎐CH); m/z 168 (Mϩ, 2%), 150 (39), 121
᎐
᎐
150 (70), 121 (34), 97 (66), 93 (40), 84 (72), 79 (68), 67 (89) and
55 (100) [Found: Mϩ, 168.1500].
(1ꢀ,2ꢁ,E)-2-(Hex-1-enyl)cyclohexanol 11b
By the foregoing method, starting with the acetylenic alcohol
10b (0.40 g), the trans-(E)-cyclohexanol 11b (0.324 g, 80%)
was obtained as an oil, νmax/cmϪ1 3330, 2928, 2856 and 970;
δH (400 MHz) 0.89 (3H, t, J 7.1, CH3), 1.14–1.83 (14H, m),
2.01–2.04 (1H, m, 2-H), 2.51 (1H, br s, OH), 3.18 (1H, ddd,
J 9.9, 9.9 and 4.2, 1-H), 5.24 (1H, dd, J 15.3 and 8.8, 1Ј-H)
and 5.58 (1H, ddd, J 15.3, 6.8 and 6.8, 2Ј-H); δC (100 MHz)
14.0 (CH3), 22.3, 24.9, 25.4, 31.6, 31.7, 32.4, 33.7 (all CH2), 50.3
᎐
᎐
(22), 111 (27), 97 (50), 93 (30), 79 (59), 67 (72), 55 (82) and 41
(100) [Found: Mϩ, 168.1476].
(2-CH), 73.1 (1-CH), 132.0 (᎐CH) and 133.7 (᎐CH); m/z 164
(1ꢁ,2ꢁ,E)-2-(Hex-1-enyl)cyclohexanol 14b
᎐
᎐
(Mϩ Ϫ H2O, 37%), 121 (30), 111 (33), 98 (46), 81 (68), 79 (69),
67 (100) and 55 (86) [Found: Mϩ Ϫ H2O, 164.1587. C12H20
requires M, 164.1565].14
Mitsunobu reaction of the cyclohexanol 10b (1.94 g, 10.6
mmol) exactly as described above, but with a final purification
by CC in 3% ether–petrol gave the nitrobenzoate ester 13b (3.01
g, 89%) as a yellow oil, νmax/cmϪ1 3054, 2935, 2861, 2228, 1723,
1607, 1529, 1343 and 873; δH (250 MHz) 0.84–0.89 (3H, m,
CH3), 1.40–2.32 (14H, m), 2.95–3.13 (1H, m, 2-H), 5.05–5.15
(1H, m, 1-H) and 8.26–8.28 (4H, m, Ar-H); δC (67.5 MHz)
13.5 (CH3), 18.3, 21.8, 22.0, 22.9 28.0, 29.7, 31.1 (all CH2), 32.9
(2-CH), 74.4 (1-CH), 79.2 (1Ј(2Ј)-C), 85.0 (2Ј(1Ј)-C), 123.4
(2 × ArCH), 130.7 (2 × ArCH), 138.7 (ArC), 151.3 (ArC)
and 164.0 (CO); m/z 329 (Mϩ, 1%), 260 (9), 162 (78), 150 (100),
104 (96), 91 (51) and 76 (53) [Found: Mϩ, 329.1637. C19H23-
NO4 requires M, 329.1627] [Found: C, 69.3; H, 7.2; N, 4.4.
C19H23NO4 requires C, 69.3; H, 7.0; N, 4.3%].
(1ꢀ,2ꢁ,Z)-2-(Hex-1-enyl)cyclopentanol 12a
Quinoline (18.6 µl) was added to a stirred suspension of 5%
palladium on barium sulfate (0.02 g) in ethyl acetate (5 ml).
After 20 min at ambient temperature, the hydroxyacetylene
10a (0.40 g) was added and the resulting suspension vigorously
stirred under an atmosphere of hydrogen for 3 h then filtered
through Kieselguhr. The combined filtrate and ethyl acetate
washings were washed with 1 M hydrochloric acid (10 ml),
saturated aqueous sodium hydrogen carbonate (10 ml) and
brine (10 ml) then dried and evaporated to leave the trans-(Z)-
cyclopentanol 12a (0.37 g, 92%) as an oil, νmax/cmϪ1 3340, 3000,
2954, 2871 and 730; δH (250 MHz) 0.90 (3H, t, J 6.9, CH3),
1.23–2.43 (13H, m), 2.57–2.72 (1H, m, 2-H), 3.78–3.80 (1H, m,
1-H), 5.21 (1H, dd, J 10.8 and 8.0, 1Ј-H) and 5.47 (1H, ddd,
J 10.8, 6.3 and 6.3, 2Ј-H); δC (67.5 MHz) 13.9 (CH3), 21.3, 22.3,
27.3, 30.5, 32.1, 33.4 (all CH2), 46.6 (2-CH), 79.3 (1-CH), 131.5
(᎐CH) and 131.9 (᎐CH); m/z 168 (Mϩ, 3%), 150 (77), 121 (84),
Reduction of the foregoing ester 13b (0.075 g, 0.23 mmol) as
described above gave the cis-(E)-cyclohexanol 14b (0.040 g,
95%) as an oil, νmax/cmϪ1 3403, 2929, 2857 and 975; δH (250
MHz) 0.90 (3H, t, J 7.0, CH3), 1.22–2.26 (16H, m), 3.78–3.80
(1H, m, 1-H), 5.51–5.55 (2H, m, 1Ј- and 2Ј-H); δC (100 MHz)
13.9 (CH3), 21.2, 22.2, 24.1, 26.5, 31.8, 32.0, 32.6 (all CH2), 44.3
(2-CH), 69.7 (1-CH), 130.7 (᎐CH) and 132.7 (᎐CH); m/z 182
᎐
᎐
᎐
᎐
93 (61), 79 (87), 67 (97) and 55 (100) [Found: Mϩ, 168.1501.
C11H20O requires M, 168.1514].
(Mϩ, 3%), 164 (51), 121 (41), 111 (39), 98 (61), 91 (43), 79 (65),
67 (100) and 55 (82) [Found: Mϩ, 182.1642].
(1ꢀ,2ꢁ,Z)-2-(Hex-1-enyl)cyclohexanol 12b
cis-2-(Hex-1-ynyl)cyclopentanol 15a
By the foregoing method, Lindlar reduction of the hydroxy-
acetylene 10b (1.82 g) gave the trans-(Z)-cyclohexanol 12b
(1.71 g, 93%) as an oil, νmax/cmϪ1 3421, 2998, 2930, 2856 and
730; δH (400 MHz) 0.90 (3H, t, J 6.9, CH3), 1.11–2.24 (15H, m),
2.27 (1H, br s, OH), 3.20 (1H, ddd, J 9.8, 9.8 and 4.4, 1-H), 5.17
(1H, dd, J 10.9 and 9.9, 1Ј-H) and 5.58 (1H, ddd, J 10.9, 7.4
and 7.4, 2Ј-H); δC (67.5 MHz) 13.9 (CH3), 22.3, 24.7, 25.1, 27.4,
31.4, 32.0, 33.4 (all CH2), 44.7 (2-CH), 73.7 (1-CH), 131.6
(᎐CH) and 133.1 (᎐CH); m/z 182 (Mϩ, 8%), 164 (75), 135 (44),
The nitrobenzoate 13a (1.00 g, 3.17 mmol) was added to a
solution of sodium hydroxide (0.634 g, 15.9 mmol) in 95%
methanol and the resulting solution stirred at ambient tem-
perature overnight, then the bulk of the solvent was evaporated.
The residue was partitioned between water (15 ml) and ether
(20 ml) and the separated aqueous layer extracted with
ether (2 × 20 ml). The combined ether solutions were dried
and evaporated. CC (5% ethyl acetate–petrol) then gave the
hydroxyacetylene 15a (0.40 g, 76%) as an oil, νmax/cmϪ1 3472,
2956, 2872 and 2233; δH (270 MHz) 0.98 (3H, t, J 7.1, CH3),
1.23–2.13 (13H, m), 2.69–2.71 (1H, m, 2-H) and 4.16–4.20
(1H, m, 1-H); δC (67.5 MHz) 13.5 (CH3), 18.4, 21.9, 22.2, 30.4,
31.1, 32.9 (all CH2), 38.4 (2-CH), 74.0 (1-CH), 78.8 (1Ј(2Ј)-C)
and 84.6 (2Ј(1Ј)-C); m/z 166 (Mϩ, 2%), 148 (11), 119 (59), 106
(46), 91 (58), 80 (100), 79 (56) and 67 (61) [Found: Mϩ,
166.1351].
᎐
᎐
121 (94), 96 (54), 81 (78), 79 (64), 67 (100) and 55 (86) [Found:
Mϩ, 182.1689. C12H22O requires M, 182.1671].14
(1ꢁ,2ꢁ,E)-2-(Hex-1-enyl)cyclopentanol 14a
Diethyl azodicarboxylate (4.62 ml, 26.5 mmol) was added
dropwise during 5 min to a stirred solution of the hydroxy-
acetylene 10a (1.00 g, 6.01 mmol), triphenylphosphine (7.57 g,
J. Chem. Soc., Perkin Trans. 1, 2000, 3469–3476
3473

View Article Online
cis-2-(Hex-1-ynyl)cyclohexanol 15b
cyclohexanol 11b (0.20 g, 1.10 mmol) for 1.3 h, followed by
CC (5% ether–petrol) gave the (2β,3α,3aα,7aβ)-iodofuran 18
(0.332 g, 98%) as a colourless oil, νmax/cmϪ1 2931, 2856, 1120,
1094 and 1075; δH (400 MHz) 0.92 (3H, t, J 7.2, CH3), 1.02 (1H,
dddd, J 12.3, 12.3, 12.3 and 3.7, 4-Hax), 1.26–1.81 (12H,
m), 1.97–2.00 (1H, m, 4-Heq), 2.00–2.07 (1H, m, 7-Heq), 3.15
(1H, ddd, J 10.5, 10.5 and 4.0, 7a-H), 3.52 (1H, dd, J 11.2 and
8.1, 3-H) and 4.20 (1H, ddd, J 8.1, 8.1 and 3.9, 2-H); δC (100
MHz) 14.0 (CH3), 22.7, 24.4, 25.3, 27.2, 28.2 (all CH2), 29.9
(3-CH), 31.5, 33.2 (both CH2), 56.2 (3a-CH), 80.7 (2-CH) and
87.1 (7a-CH); m/z 308 (Mϩ, 2%), 251 (35), 222 (22), 181 (55),
163 (17), 124 (84), 95 (100) and 81 (31) [Found: Mϩ, 308.0657.
C12H21IO requires M, 308.0637] [Found: C, 46.8; H, 6.7.
C12H21IO requires C, 46.7; H, 6.9%].
Saponification of the nitrobenzoate 13b (2.00 g) exactly as
described above gave, after CC (17% ethyl acetate–petrol) the
hydroxyacetylene 15b (0.89 g, 79%) as a colourless oil, νmax/cmϪ1
3420, 2933, 2858 and 2362; δH (270 MHz) 1.01 (3H, t, J 6.9,
CH3), 1.26–2.33 (15H, m), 2.70–2.88 (1H, m, 2-H) and 3.70–
3.72 (1H, m, 1-H); δC (67.5 MHz) 13.6 (CH3), 18.4, 21.9, 22.3,
22.7, 29.1, 31.2, 31.3 (all CH2), 35.9 (2-CH), 69.8 (1-CH), 79.5
(1Ј(2Ј)-C) and 84.4 (2Ј(1Ј)-C); m/z 180 (Mϩ, 10%), 162 (8), 137
(32), 120 (29), 105 (39), 91 (65), 79 (85), 67 (100) and 55 (54)
[Found: Mϩ, 180.1490].
(1ꢁ,2ꢁ,Z)-2-(Hex-1-enyl)cyclopentanol 16a
Lindlar reduction of the cyclopentanol 15a (0.90 g), exactly as
described above, gave the cis-(Z)-cyclopentanol 16a (0.85 g,
94%) as a colourless oil, νmax/cmϪ1 3380, 3010, 2957, 2871 and
748; δH (400 MHz) 0.91 (3H, t, J 7.1, CH3), 1.21–2.11 (13H, m),
2.67–2.74 (1H, m, 2-H), 4.13–4.15 (1H, m, 1-H), 5.39 (1H, dd,
J 10.9 and 7.3, 1Ј-H) and 5.57 (1H, ddd, J 10.9, 7.3 and 7.3,
2Ј-H); δC (100 MHz) 13.9 (CH3), 22.3 (× 2), 27.7, 30.1, 31.9,
NOE data: 2-H–3a-Hax (4.2%); 3-H–7a-Hax (5.6%); 3-H–4-
Hax (4.0%); 4-Hax–7a-Hax (5.8%); 7-Heq–7a-Hax (3.7%).
Alternative cyclisation conditions. i) The trans-(E)-cyclo-
hexanol 11b (0.20 g, 1.10 mmol) was cyclized by the general
procedure but using powdered sodium hydroxide (0.132 g,
3.33 mmol) as base in place of sodium hydrogen carbonate.
Work-up after 1.5 h followed by CC gave the (2β,3α,3aα,7aβ)-
iodofuran 18 (0.308 g, 91%) which displayed spectroscopic and
analytical data identical to the foregoing sample.
ii) The trans-(E)-cyclohexanol 11b (0.20 g, 1.10 mmol)
was cyclized by the general procedure but in the absence
of any base. Work-up after 1.5 h followed by CC gave the
(2β,3α,3aα,7aβ)-iodofuran 18 (0.271 g, 80%) which displayed
spectroscopic and analytical data identical to the foregoing
sample.
iii) To a stirred solution of the trans-(E)-cyclohexanol 11b
(0.500 g, 2.74 mmol) in dry dichloromethane (20 ml) was added
N-iodosuccinimide (0.679 g, 3.02 mmol) and the resulting
solution stirred in the dark for 5 h then the solvent evaporated.
The residue was triturated with ether (20 ml) and the resulting
suspension filtered and the filtrate evaporated. CC gave the
(2β,3α,3aα,7aβ)-iodofuran 18 (0.670 g, 79%) which displayed
spectroscopic and analytical data identical to the foregoing
sample.
34.4 (all CH ), 43.6 (2-CH), 75.9 (1-CH), 128.7 (᎐CH) and
᎐
2
133.0 (᎐CH); m/z 168 (Mϩ, 2%), 150 (73), 121 (65), 93 (61), 79
᎐
(100), 67 (89) and 55 (87) [Found: Mϩ, 168.1539] [Found: C,
78.1; H, 12.3. C11H20O requires C, 78.5; H, 12.0%].
(1ꢁ,2ꢁ,Z)-2-(Hex-1-enyl)cyclohexanol 16b
Lindlar reduction of the cyclohexanol 15b (0.40 g), exactly
as described above, gave the cis-(Z)-cyclohexanol 16b (0.38 g,
94%) as a colourless oil, νmax/cmϪ1 3394, 3009, 2930, 2856 and
733; δH (250 MHz) 0.90 (3H, t, J 6.9, CH3), 1.31–2.07 (15H, m),
2.58–2.61 (1H, m, 2-H), 3.74–3.77 (1H, m, 1-H) and 5.48–5.53
(2H, m, 1Ј- and 2Ј-H); δC (67.5 MHz) 13.9 (CH3), 21.6, 22.3,
23.4, 27.4, 28.2, 32.0, 32.1 (all CH2), 39.4 (2-CH), 70.7 (1-CH),
129.5 (᎐CH) and 132.2 (᎐CH); m/z 182 (Mϩ, 5%), 164 (67), 135
᎐
᎐
(35), 121 (63), 107 (28), 98 (54), 93 (39), 79 (77), 67 (100) and
55 (85) [Found: Mϩ, 182.1663].
General procedure for iodocyclisations
iv) The trans-(E)-cyclohexanol 11b (0.20 g, 1.10 mmol)
was cyclized by the general procedure but using triethylamine
(0.46 ml, 3.30 mmol) as base in place of sodium hydrogen
carbonate. After 30 h at 0 ЊC, no tetrahydrofuran formation
could be detected by either TLC or 1H NMR analysis.
v) The trans-(E)-cyclohexanol 11b (0.20 g, 1.10 mmol) was
cyclized by the general procedure but using N,N-diisopropyl-
ethylamine (Hünig’s base; 0.575 ml, 3.30 mmol) as base in place
of sodium hydrogen carbonate. After 30 h at 0 ЊC, no tetra-
Sodium hydrogen carbonate (0.28 g, 3.33 mmol) was stirred
with the homoallylic alcohol (1.11 mmol) in dry acetonitrile
(6 ml) at 0 ЊC for 5 min then iodine (0.845 g, 3.33 mmol) was
added in one portion and stirring continued for the time stated,
maintaining the mixture at 0 ЊC with exclusion of light. The
mixture was then diluted with ether (10 ml) and washed with
saturated aqueous sodium thiosulfate (10 ml). The aqueous
washings were extracted with ether (3 × 20 ml) and the com-
bined organic solutions dried and evaporated. The residue was
purified by CC using the specified solvents.
1
hydrofuran formation could be detected by either TLC or H
NMR analysis.
(2ꢁ,3ꢀ,3aꢀ,6aꢁ)-2-Butyl-3-iodohexahydro-2H-cyclopenta[b]-
furan 17
(2ꢀ,3ꢀ,3aꢀ,7aꢁ)-2-Butyl-3-iodooctahydrobenzofuran 20
By the general procedure, iodocyclisation of the trans-(Z)-
cyclohexanol 12b (0.22 g, 1.21 mmol) for 16 h, followed by
CC (17% ether–petrol) gave the (2α,3α,3aα,7aβ)-iodofuran 20
(0.28 g, 75%) as a colourless oil, νmax/cmϪ1 2933, 2857 and 1116;
δH (400 MHz) 0.92 (3H, t, J 7.2, CH3), 1.03 (1H, dddd, J 12.3,
12.2, 11.7 and 3.7, 4-Hax), 1.16–1.52 (9H, m), 1.66 (1H, dddd,
J 11.7, 11.0, 10.8 and 3.1, 3a-H), 1.76–1.83 (2H, m), 2.02–2.10
(2H, m, 4- and 7-Heq), 3.00 (1H, ddd, J 10.8, 10.4 and 3.9,
7a-H), 3.75 (1H, ddd, J 8.2, 8.2 and 3.9, 2-H) and 4.07 (1H,
dd, J 11.0 and 8.2, 3-H); δC (100 MHz) 14.1 (CH3), 22.6, 24.5,
25.5, 27.4, 28.8, 31.4 (all CH2), 33.5 (3-CH), 39.1 (CH2), 55.5
(3a-CH), 77.9 (2-CH) and 82.2 (7a-CH); m/z 251 (Mϩ Ϫ Bu,
11%), 222 (14), 181 (13), 124 (28), 95 (100), 85 (20), 67 (25) and
55 (20); m/z [CI Ϫ NH3] 326 (Mϩ ϩ NH4), 309 (Mϩ ϩ H), 258,
240 and 181 [Found: C, 46.6; H, 6.9. C12H21IO requires C, 46.7;
H, 6.9%].
By the general procedure, iodocyclisation of the trans-(E)-
cyclopentanol 11a (0.22 g, 1.19 mmol) for 48 h, followed by CC
(5% ether–petrol) gave the (2β,3α,3aα,6aβ)-iodofuran 17 (0.102
g, 29%) as a colourless oil, νmax/cmϪ1 2956, 2934, 2867, 1123 and
1084; δH (400 MHz) 0.92 (3H, t, J 7.2, CH3), 1.19–2.18 (12H,
m), 2.46 (1H, dddd, J 11.7, 11.5, 11.3 and 6.5, 3a-H), 3.65 (1H,
dd, J 11.5 and 8.0, 3-H), 3.73 (1H, ddd, J 11.3, 11.3 and 6.5,
6a-H) and 4.69 (1H, ddd, J 8.0, 8.0 and 3.7, 2-H); δC (100 MHz)
13.9 (CH3), 20.1, 22.6 (both CH2), 24.8 (3-CH), 25.7, 25.9, 28.1,
33.3 (all CH2), 61.9 (3a-CH), 86.8 (2-CH) and 98.0 (6a-CH);
m/z 294 (Mϩ, 3%), 208 (37), 149 (5), 110 (12), 81 (100), 79 (11),
67 (23) and 55 (13) [Found: Mϩ, 294.0492. C11H19IO requires
M, 294.0481].
NOE data: 2-H–3a-H (5.4%); 3-H–6a-H (5.3%).
(2ꢁ,3ꢀ,3aꢀ,7aꢁ)-2-Butyl-3-iodooctahydrobenzofuran 18
NOE data: 2-H–3-H (11.6%); 2-H–7a-Hax (5.7%); 2-α-CH2–
3a-H (4.3%); 3-H–7a-Hax (5.2%).
By the general procedure, iodocyclisation of the trans-(E)-
3474
J. Chem. Soc., Perkin Trans. 1, 2000, 3469–3476

View Article Online
(2ꢁ,3ꢀ,3aꢀ,6aꢀ)-2-Butyl-3-iodohexahydro-2H-cyclopenta-
[b]furan 21 and (2ꢀ,3ꢁ,3aꢀ,6aꢀ)-2-butyl-3-iodohexahydro-2H-
cyclopenta[b]furan 22
J 5.4, 5.4 and 2.6, 6a-H); δC (100 MHz) 14.0 (CH3), 22.6, 25.3,
28.1, 32.6, 34.5, 36.4, (all CH2), 40.3 (3-CH), 56.4 (3a-CH), 80.8
(2-CH) and 83.1 (6a-CH); m/z [FAB] 295 (Mϩ ϩ H, 3%), 167
(27), 136 (23), 109 (27), 95 (42), 81 (55), 69 (76), 57 (97) and 55
(100) [Found: C, 45.1; H, 6.7. C11H19IO requires C, 44.9; H,
6.5%].
By the general procedure, iodocyclisation of the cis-(E)-
cyclopentanol 14a (0.050 g, 0.297 mmol) for 1.5 h, followed by
CC (1% ether–petrol) gave i) the (2β,3α,3aα,6aα)-iodofuran 21
(0.044 g, 50%) as a colourless oil, νmax/cmϪ1 2955, 2928, 2859,
1123 and 1103; δH (400 MHz) 0.91 (3H, t, J 7.1, CH3), 1.26–1.93
(12H, m), 2.97–2.99 (1H, m, 3a-H), 3.20 (1H, dd, J 9.7 and 7.5,
3-H), 3.74 (1H, ddd, J 7.5, 7.5 and 0.4, 2-H) and 4.45 (1H, dd,
J 6.9 and 5.7, 6a-H); δC (100 MHz) 13.9 (CH3), 22.7, 23.0, 28.2,
30.7, 30.8 (all CH2), 32.2 (3-CH), 33.6 (CH2), 55.5 (3a-CH),
83.8 (6a-CH) and 86.5 (2-CH); m/z [CI–NH3] 295 (Mϩ ϩ H),
207, 168 and 92 and ii) the (2α,3β,3aα,6aα)-iodofuran 22 (0.035
g, 40%) as a colourless oil, νmax/cmϪ1 2956, 2925, 2860, 1131
and 1089; δH (400 MHz) 0.91 (3H, t, J 7.2, CH3), 1.25–1.90
(11H, m), 1.92–2.01 (1H, m, 6–H), 2.73 (1H, dddd, J 9.5, 8.9,
6.7 and 6.5, 3a-H), 3.82 (1H, ddd, J 7.2, 7.2 and 2.6, 2-H), 3.89
(1H, dd, J 9.5 and 7.2, 3-H) and 4.54 (1H, ddd, J 6.5, 6.2 and
3.4, 6a-H); δC (100 MHz) 14.0 (CH3), 22.7, 24.9, 28.1, 31.6 (all
CH2), 32.9 (3-CH), 33.8 (CH2), 35.6 (6-CH2), 48.4 (3a-CH),
82.8 (6a-CH) and 83.5 (2-CH); m/z [CI Ϫ NH3] 312 (Mϩ ϩ
NH4), 295 (Mϩ ϩ H), 167 and 91.
NOE data: 2-H–3-H (7.2%); 3-H–3a-H (4.0%); 3a-H–6a-H
(7.2%).
(2ꢀ,3ꢀ,3aꢀ,7aꢀ)-2-Butyl-3-iodooctahydrobenzofuran 26
By the general procedure, iodocyclisation of the cis-(Z)-
cyclohexanol 16b (0.156 g, 0.856 mmol) for 22 h, followed by
CC (5% ether–petrol) gave the (2α,3α,3aα,7aα)-iodofuran 26
(0.248 g, 94%) as a colourless oil, νmax/cmϪ1 2931, 2858 and
1119; δH (400 MHz) 0.91 (3H, t, J 7.1, CH3), 1.16–2.07 (14H,
m), 2.49–2.61 (1H, m, 3a-H), 3.63 (1H, ddd, J 6.2, 6.2 and 4.4,
2-H), 4.32 (1H, dd, J 4.4 and 1.9, 3-H) and 4.52 (1H, app.
q, J 3.8, 7a-H); δC (100 MHz) 14.0 (CH3), 20.4, 22.6, 23.5,
28.2, 28.4 (× 2), 39.6 (all CH2), 41.1 (3-CH), 50.7 (3a-CH), 74.5
(7a-CH) and 79.0 (2-CH); m/z [FAB] 309 (Mϩ ϩ H, 14%), 291
(16), 181 (45), 165 (40), 109 (44), 95 (72), 81 (81), 67 (67) and
55 (100) [Found: C, 46.6; H, 6.9. C12H21IO requires C, 46.7;
H, 6.9%]
By the general procedure, iodocyclisation of the cis-(E)-
cyclopentanol 14a (0.100 g, 0.601 mmol) for 5 h at Ϫ78 ЊC in
a mixture of acetonitrile (3 ml) and dichloromethane (12 ml)
gave the same two iodofurans (21 and 22) (0.156 g, 88%) in a
ratio of 1.3:1 which exhibited spectroscopic data identical to
the foregoing compounds.
NOE data: (2β,3α,3aα,6aα)-iodofuran 21 2-H–3a-H (3.4%);
2-H–6a-H (4.1%); 3a-H–6a-H (7.4%); (2α,3β,3aα,6aα)-iodo-
furan 22 3-H–3a-H (11.7%); 3a-H–6a-H (7.6%).
NOE data: 2-H–3-H (8.5%); 3-H–3a-H (4.2%); 3a-H–7a-H
(8.5%).
(2ꢁ,3ꢀ,3aꢀ,7aꢁ)-3-Bromo-2-butyloctahydrobenzofuran 33
N-Bromosuccinimide (0.351 g, 1.97 mmol) was added in one
portion to a stirred solution of the trans-(E)-cyclohexanol
11b (0.30 g, 1.65 mmol) in dry carbon tetrachloride (10 ml) at
ambient temperature. The resulting mixture was refluxed for
4 h, then cooled and the solvent evaporated. CC (5% ether–
petrol) of the residue gave the (2β,3α,3aα,7aβ)-bromofuran 33
(0.297 g, 69%) as a colourless oil, νmax/cmϪ1 2937, 2859, 1095
and 1076; δH (250 MHz) 0.92 (3H, t, J 6.9, CH3), 1.02–2.12
(15H, m), 3.22 (1H, ddd, J 10.6, 10.5 and 4.0, 7a-H), 3.57
(1H, dd, J 10.7 and 7.6, 3-H) and 4.08 (1H, ddd, J 7.6, 7.6 and
4.3, 2-H); δC (62.5 MHz) 14.1 (CH3), 22.7, 24.2, 25.4, 26.9, 28.2,
32.0, 34.0 (all CH2), 54.1 (3(3a)-CH), 54.9 (3a(3)-CH), 80.6
(2(7a)-CH) and 86.1 (7a(2)-CH); m/z 262 (Mϩ (Br81), 6%), 260
(Mϩ (Br79), 6), 205 (39), 203 (41), 176 (36), 174 (38), 123 (38), 95
(100), 81 (95) and 67 (53) [Found: C, 55.2; H, 7.6. C12H21BrO
requires C, 55.4; H, 8.1%].
(2ꢁ,3ꢀ,3aꢀ,7aꢀ)-2-Butyl-3-iodooctahydrobenzofuran 23
By the general procedure, iodocyclisation of the cis-(E)-
cyclohexanol 14b (0.080 g, 0.44 mmol) for 5 h, followed by CC
(1% ether–petrol) gave the (2β,3α,3aα,7aα)-iodofuran 23 (0.115
g, 73%) as a colourless oil mixed with an inseparable isomer, in
a ratio of 5:1. The mixture showed νmax/cmϪ1 2930, 2855, 1146,
1116 and 1088; m/z [FAB] 309 (Mϩ ϩ H, 15%), 211 (8), 181
(24), 154 (41), 137 (32), 95 (38), 81 (65), 69 (59) and 55 (100)
[Found: C, 46.7; H, 6.8%]. The major isomer 23 showed δH (400
MHz) 0.92 (3H, t, J 7.2, CH3), 1.30–1.74 (14H, m), 2.35–2.43
(1H, m, 3a-H), 3.66 (1H, dd, J 6.6 and 5.1, 3-H), 4.04–4.08 (1H,
m, 7a-H) and 4.26 (1H, ddd, J 7.0, 7.0 and 5.1, 2-H); δC (100
MHz) 14.0 (CH3), 21.4, 22.9, 23.2, 27.3, 28.3, 29.1 (all CH2),
32.1 (3-CH), 34.7 (CH2), 49.9 (3a-CH), 75.5 (7a-CH) and 88.7
(2-CH). The minor isomer (24) showed δC (100 MHz) 14.0
(CH3), 19.9, 22.9, 25.0, 28.4, 28.9 (all CH2), 33.1 (3-CH), 33.9,
34.7 (both CH2), 43.0 (3a-CH), 74.5 (7a-CH) and 84.5 (2-CH).
By the general procedure, iodocyclisation of the cis-(E)-
cyclohexanol 14b (0.100 g, 0.549 mmol) for 2.5 h at Ϫ78 ЊC in
a mixture of acetonitrile (3 ml) and dichloromethane (12 ml)
gave the same two iodofurans (23 and 24) (0.166 g, 98%) in a
ratio of 10:1 which exhibited spectroscopic data identical to the
foregoing compounds.
(2ꢀ,3ꢁ,3aꢀ,7aꢁ)-2-Butyl-3-formyloxyoctahydrobenzofuran 34
To a stirred solution of the (2α,3α,3aα,7aβ)-iodofuran 20
(0.060 g, 0.195 mmol) in dry N,N-dimethylformamide (10 ml)
was added silver tetrafluoroborate (0.076 g, 0.39 mmol). The
resulting mixture was stirred at 70 ЊC for 48 h, then cooled,
diluted with ether (10 ml) and filtered through Kieselguhr.
The solid was washed with ether (2 × 5 ml) and the combined
filtrates washed with 1 M hydrochloric acid (15 ml), saturated
aqueous sodium bicarbonate (15 ml) and brine (15 ml) then
dried and evaporated. CC (10% ether–petrol) separated the
formyloxy-THF 34 (0.028 g, 64%) as a colourless oil, νmax/cmϪ1
2932, 2860, 1726, 1174 and 1067; δH (400 MHz) 0.92 (3H, t,
J 7.0, CH3), 1.19–1.23 (1H, m, 7-Heq), 1.30–1.35 (1H, m, 3a-H),
1.21–1.82 (12H, m), 2.17–2.20 (1H, m, 7-Hax), 3.41 (1H,
ddd, J 10.6, 10.6 and 3.9, 7a-H), 3.83 (1H, dd, J 6.6 and 6.6,
2-H), 5.08 (1H, app. d, J 5.1, 3-H) and 8.08 (1H, app. s, CHO);
δC (100) 14.0 (CH3), 22.7, 23.9, 25.4, 27.7, 29.7, 31.7, 34.0
(all CH2), 48.2 (3a-CH), 79.0, 80.3, 85.0 (all CH) and 160.6
(CO); m/z 180 (Mϩ Ϫ HCO2H, 11%), 169 (22), 138 (56),
123 (29), 112 (37), 94 (100), 79 (39), 69 (21), 67 (25) and 55
(25) [Found: Mϩ Ϫ HCO2H, 180.1499. C12H20O requires M,
180.1514]; m/z [FAB] 197 (Mϩ ϩ H Ϫ HCO, 16%), 181 (34),
123 (21), 107 (37), 95 (27), 81 (36), 68 (34) and 56 (57) [Found:
Mϩ ϩ H Ϫ HCO, 197.1567. C12H21O2 requires M, 197.1542].
NOE data for (2β,3α,3aα,7aα)-iodofuran 23: 2-H–3a-H
(2.8%); 2-H–7a-H (4.1%); 3a-H–7a-H (6.3%).
(2ꢀ,3ꢀ,3aꢀ,6aꢀ)-2-Butyl-3-iodohexahydro-2H-cyclopenta-
[b]furan 25
By the general procedure, iodocyclisation of the cis-(Z)-
cyclopentanol 16a (0.050 g, 0.297 mmol) for 24 h, followed by
CC (5% ether–petrol) gave the (2α,3α,3aα,6aα)-iodofuran 25
(0.084 g, 96%) as a colourless oil, νmax/cmϪ1 2956, 2930, 2871,
2864 and 1153; δH (400 MHz) 0.91 (3H, t, J 7.1, CH3), 1.25–1.90
(12H, m), 3.04 (1H, ddd, J 6.5, 6.5 and 3.5, 2-H), 3.13–3.19 (1H,
m, 3a-H), 4.20 (1H, dd, J 3.5 and 2.0, 3-H) and 4.76 (1H, ddd,
J. Chem. Soc., Perkin Trans. 1, 2000, 3469–3476
3475

View Article Online
NOE data: 2-H–3-H (2.7%); 2-H–7a-H (4.7%); 3-H–3a-H
(13.6%).
combined extracts were washed with water (4 × 10 ml) then
dried and evaporated. CC (1% ether–petrol) separated the
sulfide 41 (0.043 g, 45%) as a colourless oil, νmax/cmϪ1 3057,
2932, 2858, 1146 and 1075; δH (400 MHz) 0.81 (3H, t, J 7.1,
CH3), 1.05–1.19 (1H, m, 7-Heq), 1.06–1.74 (11H, m), 1.44 (1H,
dddd, J 12.1, 12.1, 12.1 and 3.4, 4-Hax), 1.80–1.87 (1H, m,
3a-H), 2.07–2.10 (1H, m, 7-Hax), 3.49 (1H, ddd, J 10.6, 10.6 and
5.9, 7a-H), 3.78 (1H, dd, J 5.0 and 5.0, 3-H), 4.19–4.24 (1H, m,
2-H), 7.05–7.25 (3H, m) and 7.31 (2H, d, J 7.3); δC (100 MHz)
14.0 (CH3), 22.8, 23.9, 25.3 (all CH2), 26.6 (4-CH2), 28.9 (CH2),
32.1 (7-CH2), 32.7 (CH2), 51.3 (3a-CH), 55.2 (3-CH), 79.8 (7a-
CH), 82.2 (2-CH), 126.0 (4Ј-CH), 128.8 (2 × 3Ј-CH), 130.0
(2 × 2Ј-CH) and 137.2 (1Ј-C); m/z [FAB] 291 (Mϩ ϩ H, 64%),
290 (86), 289 (54), 204 (85), 181 (66), 123 (45), 95 (87), 81 (76),
68 (67) and 56 (100) [Found: Mϩ, 290.1703. C18H26OS requires
M, 290.1704].
(2ꢁ,3ꢁ,3aꢀ,7aꢁ)-2-Butyl-3-formyloxyoctahydrobenzofuran 35
The foregoing method starting with the (2β,3α,3aα,7aβ)-iodo-
furan 18 (0.049 g, 0.161 mmol) gave the formyloxy-THF 35
(0.028 g, 77%) as a colourless oil, νmax/cmϪ1 2934, 2861, 1727
and 1174; δH (400 MHz) 0.89 (3H, t, J 7.1, CH3), 1.17–1.21
(1H, m, 7-Heq), 1.56–1.64 (1H, m, 3a-H), 1.17–1.80 (12H, m),
2.09–2.19 (1H, m, 7-Hax), 3.52 (1H, ddd, J 10.8, 10.8 and 4.0,
7a-H), 4.15 (1H, ddd, J 8.5, 4.2 and 4.2, 2-H), 5.52 (1H, dd,
J 4.2 and 4.0, 3-H) and 8.16 (1H, app. s, CHO); δC (100 MHz)
14.0 (CH3), 22.7, 23.9, 24.4, 25.3, 28.6, 29.7, 32.0 (all CH2),
49.7 (3a-CH), 75.3, 79.5, 81.4 (all CH) and 160.4 (CO); m/z
[FAB] 227 (Mϩ ϩ H, 14%), 226 (6), 225 (32), 181 (100),
154 (24), 137 (30), 107 (22), 95 (44), 85 (61), 81 (63), 66 (44)
and 54 (63) [Found: Mϩ ϩ H, 227.1657. C13H23O3 requires M,
227.1647].
Acknowledgements
NOE data: 2-H–3-H (9.8%); 2-H–3a-H (6.4%); 3-H–3a-H
(6.9%); 7-Heq–7a-Hax (6.2%).
We are grateful to Glaxo Wellcome Research and Development
Ltd and the EPSRC for financial support under the CASE
Award Scheme.
(2ꢁ,3ꢁ,3aꢀ,7aꢁ)-3-Azido-2-butyloctahydrobenzofuran 40
References
Sodium azide (0.042 g, 0.649 mmol) was added in one portion
to a stirred solution of (2β,3α,3aα,7aβ)-iodofuran 18 (0.200 g,
0.649 mmol) in dry N,N-dimethylformamide (15 ml) and the
resulting mixture heated at 110 ЊC for 73 h (TLC monitoring).
The cooled solution was diluted with ether (20 ml) and water
(20 ml) and the resulting layers separated. The aqueous
layer was extracted with ether (2 × 20 ml) and the combined
organic solutions washed with water (4 × 20 ml) then dried and
evaporated. CC (5% ether–petrol) of the residue gave the azide
40 (0.091 g, 63%) as a colourless oil, νmax/cmϪ1 2936, 2861, 2101
and 1146; δH (400 MHz) 0.92 (3H, t, J 7.1, CH3), 1.19–1.25
(1H, m, 7-Heq), 1.57–1.64 (1H, m, 3a-H), 1.20–1.80 (12H, m),
2.04–2.14 (1H, m, 7-Hax), 3.44 (1H, ddd, J 11.9, 10.6 and 4.0,
7a-H), 3.98 (1H, dd, J 4.2 and 4.0, 3-H) and 4.07–4.12 (1H, m,
2-H); δC (67.5 MHz) 14.0 (CH3), 22.8, 23.9, 24.9, 25.3, 28.7,
30.9, 31.9 (all CH2), 50.8 (3a-CH), 66.9 (3-CH), 79.2 and 82.1
(2- and 7a-CH) and 160.4 (CO); m/z 167 (Mϩ Ϫ Bu, 3%), 138
(9), 108 (22), 85 (68), 82 (48), 67 (100), 57 (50) and 54 (38)
[Found: C, 64.5; H, 9.4; N, 18.4. C12H21N3O requires C, 64.5; H,
9.5; N, 18.8%].
1 S. B. Bedford, K. E. Bell, F. Bennett, C. J. Hayes, D. W. Knight and
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NOE data: 2-H–3-H (11.4%); 2-H–3a-H (5.0%); 3-H–3a-H
(8.6%).
(2ꢁ,3ꢁ,3aꢀ,7aꢁ)-2-Butyl-3-(phenylsulfanyl)octahydrobenzofuran
41
Sodium hydride (0.020 g of a 60% dispersion in oil, 0.487
mmol) was washed with dry pentane (3 × 3 ml) and dried under
a flow of nitrogen. A solution of thiophenol (50 µl, 0.487
mmol) in dry N,N-dimethylformamide (10 ml) was then added
dropwise and the resulting mixture stirred for 10 min at ambient
temperature. A solution of the (2β,3α,3aα,7aβ)-iodofuran 18
(0.100 g, 0.324 mmol) in dry N,N-dimethylformamide (5 ml)
was then added and the resulting mixture heated at 55 ЊC for
30 h (TLC monitoring). The cooled mixture was carefully diluted
with water (10 ml) and extracted with ether (2 × 10 ml). The
14 A. Alexakis, D. Jachiet and J. F. Normant, Tetrahedron, 1986, 42,
5607.
3476
J. Chem. Soc., Perkin Trans. 1, 2000, 3469–3476